This is the second competing renewal of our Program Project Grant, "Drugs of Abuse: Role of Protein phosphorylation" (DA 10044), which was initially funded in 1996 and again in 2001. The grant has been highly successful based on research productivity and initiation of new research projects. The overall objective of the Program Project Grant remains the same as the original, namely, to elucidate the molecular basis of the actions of drugs of abuse, particularly psychostimulants, in the dorsal striatum and nucleus accumbens. The addictive properties of drugs of abuse such as psychostimulants depend on their ability to augment dopamine neurotransmission in the basal ganglia. The Program Project Grant is organized in four Projects, a Scientific Core and an Administrative Core. The Administrative Core staff will support the integration of the researchers and institutions involved in the Program Project Grant. The main goal of the Scientific Core is to provide a research and technical support facility for all of the Program projects. Responsibilities of the Scientific Core will include the creation, characterization, and breeding of genetically altered animals;the design and execution of yeast two-hybrid studies;the production and maintenance of key reagents stocks and new reagents; and the performance of certain routine tasks required to accomplish the studies described in Projects IIV. Project I, "Psychostimulants and Dendritic spines," will focus on the role five regulators of actin dynamics play as targets of psychostimulants in the dendritic spines. Project II, "The Role of DARPP- 32, CK1, and CK2 in Mediating the Molecular and Behavioral Effects of Drugs of Abuse," will extend previous studies of four key phosphorylation sites of DARPP-32 upon in vivo administration of drugs of abuse and chronic exposure to drugs of abuse. Project III, "Striatal Phosphoproteins and the Actions of Psychostimulants," which will be a subcontract carried out at Yale University School of Medicine, study the role(s) of RCS and ARPP-16 in mediating or modulating the actions of psychostimulants as well as study the roles of the three isoforms of PP1 (PPl&#8704;, &#8707;&#61472;and &#61480;) in the actions of psychostimulants. Project IV, "The Role of GPCR-interacting Proteins in the Actions of Pscyhostimulants," will utilize yeast twohybrid screening to further investigate the multiple intracellular signaling pathways of GPCR and its protein-interacting subunits in mediating actions of cocaine, D-amphetamine, ecstasy and caffeine.